http://hdl.handle.net/10366/4155 2026-05-06T08:47:34Z http://hdl.handle.net/10366/170166 [EN]A new route to racemic diethyl 2-methyl-bicyclo[3.1.1]hept-2-ene-6,6- dicarboxylate (±)-1a by means of a palladium-catalyzed intramolecular allylic alkylation exercised on malonate-ester derivatives has been developed from R-(-)-carvone. The stereocontrolled synthesis of the enantiomerically pure (-)-1b by application of a six-step reactions sequence with a 28% overall yield from acetal 8, has been accomplished. 2010-01-01T00:00:00Z http://hdl.handle.net/10366/169771 [ES] Esta Tesis Doctoral se centra en el diseño y síntesis de nuevos iminoazúcares con potencial actividad como inhibidores de glicosidasas. Se ha desarrollado una metodología sintética eficiente para obtener sistemas oxa-nor-tropánicos en un solo paso mediante una reacción intramolecular tipo dominó basada en una cicloadición [3+2]-dipolar inicial. En el primer capítulo se estudia esta reacción entre diversas nitronas y alquenos funcionalizados, logrando acceder a sistemas oxa-nor-tropánicos y a estructuras bicíclicas de tipo indolizidina y pirrolo[1,2-a]azepina, cuya formación depende de la naturaleza de los reactivos empleados. El segundo capítulo aborda el diseño asistido por ordenador de análogos estructurales de la swainsonina, mediante estudios de fragmentación molecular (FMO) y docking, identificando compuestos con interacciones favorables en el sitio activo de la -manosidasa II de Golgi y propiedades fisicoquímicas adecuadas para su posible actividad inhibidora. En el tercer capítulo se desarrollan metodologías sintéticas regio- y diastereoselectivas para la funcionalización de los sistemas tropánicos e indolizidínicos, aprovechando la reactividad del grupo N,O-acetal para introducir sustituyentes en posición C-3 y explorando también la funcionalización en C-5. Estas transformaciones permiten obtener una amplia variedad de derivados con potencial biológico. En conjunto, el trabajo combina estrategias de síntesis orgánica y modelización molecular para avanzar en el desarrollo racional de inhibidores de glicosidasas basados en iminoazúcares. 2025-01-01T00:00:00Z http://hdl.handle.net/10366/164322 [EN]The general objective of this Thesis is the design and synthesis of moieties that can be attached to antineoplastic drugs, to produce anticancer prodrugs able of selectively attacking cancer cells without affecting healthy ones. The generated prodrugs activation is due to cancer microenvironment features exploitation, in which the drug carriers are functionalised with a disulfide bond or a nitro group, the latter can be reduced under the intrinsic factors such as hypoxia and the high concertation of glutathione for an in-situ release of the cytotoxic drug. As a result, side effects of conventional chemotherapy could be avoided. In addition to the above, the afforded prodrugs could be theranostic agents thanks to the fluorescent effect of the cyclized trigger obtained following the prodrug cleavage under the mentioned conditions. The molecular trigger was also employed as a new protecting group for amines and amino acids. These prodrugs were functionalized to be soluble in aqueous media to avoid the problems of many anticancer drugs which are known to be hydrophobic. 2025-02-04T00:00:00Z http://hdl.handle.net/10366/160431 [EN]Agents that cause apoptotic cell death by interfering with tubulin dynamics, such as vinblastine and paclitaxel, are an important class of chemotherapeutics. Unfortunately, these compounds are substrates for multidrug resistance (MDR) pumps, allowing cancer cells to gain resistance to these chemotherapeutics. The indolesulfonamide family of tubulin inhibitors are not excluded by MDR pumps and have a promising activity profile, although their high lipophilicity is a pharmacokinetic limitation for their clinical use. Here we present a new family of N-indolyl-3,4,5- trimethoxybenzenesulfonamide derivatives with modifications on the indole system at positions 1 and 3 and on the sulfonamide nitrogen. We synthesized and screened against HeLa cells 34 novel indolic benzenesulfonamides. The most potent derivatives (1.7 – 109 nM) were tested against a broad panel of cancer cell lines, which revealed that substituted benzenesulfonamides analogs had highest potency. Importantly, these compounds were only moderately toxic to nontumorigenic cells, suggesting the presence of a therapeutic index. Consistent with known clinical anti-tubulin agents, these compounds arrested the cell cycle at G2/M phase. Mechanistically, they induced apoptosis via caspase 3/7 activation, which occurred during M arrest. The substituents on the sulfonamide nitrogen appeared to determine different mechanistic results and cell fates. These results suggest that the compounds act differently depending on the bridge substituents, thus making them very interesting as mechanistic probes as well as potential drugs for further development. 2024-01-01T00:00:00Z http://hdl.handle.net/10366/159160 [ES] Esta tesis pretende conectar el mundo de la síntesis orgánica pura con el universo del descubrimiento de fármacos, ampliando el espacio químico a través de nuevas vías sintéticas que conduzcan a estructuras potencialmente activas biológicamente. El estudio de la reactividad de las isoxazolidinas quirales ha despertado un gran interés en nuestro grupo de investigación durante los últimos años. Estos conocidos heterociclos han demostrado ser materiales de partida muy versátiles para desarrollar metodologías sintéticas aún por descubrir que permitan obtener valiosas estructuras basadas en el nitrógeno. Se describe cómo se sintetizaron nuevas isoxazolidinas quirales mediante reacciones de cicloadición 1,3-dipolar, estableciendo así diversos procedimientos sintéticos para su obtención superando los problemas reportados anteriormente. Los diferentes grupos unidos al núcleo de la isoxazolidina modulan la reactividad de toda la estructura, lo que convierte a estos heterociclos en sustratos prometedores para la síntesis orientada a la diversidad (DOS). De este modo, se sintetizaron nuevos análogos tropánicos mediante una innovadora reacción de reordenamiento a partir de isoxazolidinas derivadas de lactonas, y se evaluaron como inhibidores del transportador de dopamina (DAT). Además, se llevó a cabo un diseño virtual de fármacos para idear los mejores inhibidores de DAT que podrían obtenerse mediante esta metodología de reordenamiento. Por otro lado, se obtuvo un intermedio sintético versátil a partir de nitro-isoxazolidinas, una nitroenamina. A través de este valioso compuesto se desarrollaron nuevas vías sintéticas para obtener potenciales aza-heterociclos bioactivos, allanando así el camino para el futuro del descubrimiento de fármacos. 2024-01-01T00:00:00Z http://hdl.handle.net/10366/154289 [EN]Radical cascade cyclizations of unsaturated epoxy­nitriles induced by titanocene chloride proceed in good yields and with excellent diastereoselectivities. From three to seven stereocenters were created by the reaction and a single isomeric product was obtained from most of the substrates examined. The relative configuration of the products is consistent with cyclization occurring via a chair-like transition state. The termination of the radical cascade reaction by 4-exo, 5-exo or 6-exo cyclization onto nitrile is remarkable. 2007-01-01T00:00:00Z http://hdl.handle.net/10366/154245 [EN]A practical, short, and diastereoselective synthesis of the azadiradione BCDE fragment from a readily available starting material is described. The key step was the titanocene(III)-promoted tandem cyclization of unsaturated epoxy nitrile. 2013-01-01T00:00:00Z http://hdl.handle.net/10366/154243 [EN]Highly efficient syntheses of the anti-cancer agent trans-β-elemene have been achieved by using the readily available (±)-limonene as starting material. The syntheses were achieved in only nine to eleven steps with good overall yields. The key step in these reaction sequences is a stereoselective radical cyclization, induced by titanocene chloride. 2018-01-01T00:00:00Z http://hdl.handle.net/10366/154242 [EN]The reaction of several stereoisomeric epoxy alcohols, obtained from R-(−)-carvone, and their corresponding formates, acetates, and benzoates, promoted by Cp2TiCl has been studied. The different outcomes of the reaction of epoxy derivatives are rationalized in terms of mechanistically biased processes. The radicals emerging from oxirane cleavage provide two types of reaction: dehydroxylation (deoxycarbonylation) and dehydrogenation. The results offer considerable support for the radical elimination theory of hydroxyl, formyloxyl, and acetoxyl groups. The inability of tertiary radicals to be reduced by the Ti(III) complex is demonstrated unequivocally. 2013-01-01T00:00:00Z http://hdl.handle.net/10366/154228 [EN]A practical, brief and selective synthesis of several pinene oxide derived terpenoids can be achieved from readily available starting materials. The key step is a radical reaction promoted by titanocene chloride. 2011-01-01T00:00:00Z http://hdl.handle.net/10366/154222 [EN]A new radical clock based on pinene derivatives has been designed to measure the radical cyclization rate onto cyano and carbonyl groups and the radical elimination rate of OR and CN. In this system, the known rate constant of cyclobutylcarbinyl radical cleavage is used as the internal clock. At room temperature, the cyclization rate constants for 4-exo and 5-exo processes onto nitrile and aldehyde carbonyl groups are in the order of 107 to 108 s-¹. The radical elimination rate constants for CN, OH, OCHO, and OAc are in the order of 105 to 108 s-¹. 2008-01-01T00:00:00Z http://hdl.handle.net/10366/154213 [EN]A titanocene-mediated intramolecular radical addition of different epoxy vinyl- and allylsulfones has been achieved. Five- and six-membered ring products were obtained in good to excellent yields in the presence of both 2.2 and 0.2 equiv of Cp2TiCl. A novel double-activation strategy allowed us to achieve small-size rings such as cyclobutanes and cyclopropanes. 2015-01-01T00:00:00Z http://hdl.handle.net/10366/154211 [EN]A radical coupling reaction of diverse vinyl sulfones and epoxides was mediated by Cp2TiCl (Cp = cyclopentadienyl) to provide a straightforward synthetic pathway to hydroxy sulfones. The reaction was successfully achieved by using either an excess or a catalytic amount of the TiIII reagent. The scope of the reaction was studied for several different functionalized and substituted epoxides and vinyl sulfones. 2015-01-01T00:00:00Z http://hdl.handle.net/10366/154182 [EN]The reaction of a series of 2,3-epoxy alcohols and the corresponding formates, acetates, and benzoates promoted by Cp2TiCl has been studied. The different outcome of the reaction of epoxy derivatives has been rationalized in terms of mechanistically biased processes. After homolytic oxirane cleavage, four main types of reaction were found: dehydroxylation, decarboxylation, dehydrogenation, and deoxygenation. The reaction products varied according to the substitution pattern. The radical nature of these eliminations is demonstrated. 2010-01-01T00:00:00Z http://hdl.handle.net/10366/154181 [EN]A practical, brief and selective synthesis of limonoid CDE fragments from a readily available starting diketone is described. The key step is a cationic electrocyclization promoted by strong acids. In general the methodology has been demonstrated for compounds with sensitive furane and thiophene substituents to obtain diverse substituted indenones. Several of the compounds obtained show significant antifeedant activity against Spodoptera littoralis. 2010-01-01T00:00:00Z http://hdl.handle.net/10366/154179 [EN]Radical couplings of epoxides and nitriles mediated by Cp2TiCl provide a diastereoselective route to the synthesis of β-hydroxyketones. The conditions of this “aldol-like” reaction are mild enough to avoid the dehydration of the β-hydroxyketone. The scope of the coupling reaction with functionalized and tetrasubstituted epoxides has been studied. The radical character of the coupling reactions is demonstrated. 2009-01-01T00:00:00Z